EP0560408A1 - Enantio- und regioselektive Synthesen von organischen Verbindungen mit Enolestern wie irreversibele Transacylierungs-Reagenzien - Google Patents

Enantio- und regioselektive Synthesen von organischen Verbindungen mit Enolestern wie irreversibele Transacylierungs-Reagenzien Download PDF

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EP0560408A1
EP0560408A1 EP19930107522 EP93107522A EP0560408A1 EP 0560408 A1 EP0560408 A1 EP 0560408A1 EP 19930107522 EP19930107522 EP 19930107522 EP 93107522 A EP93107522 A EP 93107522A EP 0560408 A1 EP0560408 A1 EP 0560408A1
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acetate
vinyl
ppl
alcohol
reaction
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French (fr)
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EP0560408B1 (de
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Chi-Huey Wong
Yi-Fong Wang
William J. Hennen
Kevin Anthony Babiak
John H. Dygos
John S. Ng
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GD Searle LLC
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/02—Monosaccharides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P9/00—Preparation of organic compounds containing a metal or atom other than H, N, C, O, S or halogen

Definitions

  • the present invention relates to enantio- and regioselective synthesis of esters of alcohols, sugars, organometallics and glycosides and to their preparation using enzyme mediated transesterification. More particularly, the present invention relates to enzyme catalyzed irreversible transesterification using enol esters as transacylation reagents.
  • Hydrolytic enzymes such as lipases, esterases, and proteases have been used extensively as catalysts in enantioselective syntheses.
  • the method of the present invention blocks the progress of the reverse reaction.
  • the present invention is a process for irreversible regio- and stereoselective enzyme catalyzed acylation of alcohols using enol esters as acylating reagents.
  • the present invention permits the selective modification of hydroxyl group(s) of chiral and meso alcohols, including sugars, organometallics and glycosides.
  • the enol freed upon transesterification rapidly tautomerizes to the corresponding volatile aldehyde or ketone thereby preventing the reverse reaction from occurring.
  • NMR Nuclear magnetic resonance
  • spectra were recorded on a Varian XL-200E spectrometer. All chemical shifts were reported in ppm using tetramethylsilane as an internal standard unless otherwise indicated. Rotations were determined on a Perkin Elmer 240 polarimeter.
  • Gas chromatographic (GC) analyses were performed on a Hewlett-Packard 5890 instrument with a 20-m DB-5 megabore column.
  • the lipases from Pseudomonas species (PSL, Type XIII), porcine pancreas (PPL, Type II), and Candida cylindracea (CCL, Type VII) were obained from Sigma Chemical Company. Cholesterol esterase was obtained from Amano Pharmaceutical Company.
  • Vinyl acetate ( 5/Kg, bp 72°C) and isopropenyl acetate ( 25/Kg, bp 94°C) were from Aldrich Chemical Co.
  • Vinyl propionate ( 25/25 g, bp 93-94°C) was from Pfaltz and Bauer, Inc. Some experimental protocols are described in Tables 1, 3 and 4.
  • the mixture then was heated to reflux under an atmosphere of argon for 10 h, after which time all of the valeric acid had been consumed as evidenced by capillary GC.
  • the reaction mixture was allowed to cool to room temperature and 0.5 g of sodium bicarbonate was added to quench the acid catalyst.
  • the isopropenyl acetate then was removed by evaporation under reduced pressure.
  • the orange liquid remaining was poured into 300 mL of 0°C saturated sodium bicarbonate which was overlayed with 100 mL of diethyl ether.
  • the mixture was stirred vigorously and the ether layer was analyzed by GC for the disappearance of the mixed valeric acetic anhydride.
  • Structures 15 and 16 of Table 2 represent compounds wherein excessive steric hindrance is present.
  • the alcohol substrate and an excess of enol ester were dissolved in an organic solvent, such as pyridine or a less polar solvent. After a catalytic amount of enzyme was added, the suspension was stirred at 28°C and the reaction was monitored by GC for conversion. Once the required extent of conversion was reached, the enzyme was filtered off and the solvent was removed by evaporation in a vacuum. The ester product and the unreacted alcohol were separated by chromatography on a silica gel column.
  • an organic solvent such as pyridine or a less polar solvent.
  • esters e.g, acyl sugars
  • esters can be obtained only in nearly anhydrous solvents due to thermodynamic reasons, or because of the lack of appropriate esterases to use in obtaining such esters via hydrolysis (e.g., (S)-3 in FIG. 3 and (R)-6 in FIG. 4).
  • the (R)-propionate ester obtained in toluene is stable towards solvolysis, while in ethanol or water, the ester decomposes to ferrocenylethylether or ferrocenylethanol.
  • Example 1 PSL-catalyzed transesterification of 2-0-benzylglycerol (2 of FIG. 3) with isopropenyl acetate (1a of FIG. 2)
  • Chiral 3-0-acetyl-2-0-benzylglycerol ((R)- or (S)-3 of FIG. 3), and 3-0-acetyl-2-N-benzyloxycarbonyl serinol ((R) or (S) -6 of FIG. 5), are considered to be useful building blocks for the preparation of enantiomerically pure, biologically active molecules such as phospholipids, PAF (platelet-activating factor), phospholipase A2 inhibitors, sphingoglycolipids and many others.
  • PAF platelet-activating factor
  • phospholipase A2 inhibitors phospholipase A2 inhibitors
  • sphingoglycolipids and many others.
  • the prochiral diols, 2-0-benzylglycerol (2 of FIG. 3) and 2-N-benzyloxycarbonyl (Z) serinol were chosen as substrates, respectively.
  • the diols, monoesters, and diesters were determined by GC analysis at a certain degree of conversion.
  • the enantiomeric compositions of monoesters were determined by NMR analysis. As predicted, when the reaction was terminated at 71.5% conversion (a 50% conversion corresponds to the hydrolysis of one acetate group), the optical purity of the monacetate (S)-3 obtained was 96% (the isolated chemical yield was 53%).
  • (R)-3 can be prepared from 2-0-benzylglycerol diacetate via a lipoprotein lipase-catalyzed hydrolysis.
  • the same enantioselectivity in the hydrolysis of the diacetate (4 of FIG. 3) was observed with PSL and (R)-3 was obtained in 52% yield with 71% ee.
  • (S)-3 (91% ee) was suspended in phosphate buffer (0.1 M, pH 7) at 28°C without enzyme, the optical purity was found to decrease 2-2.5% per hour.
  • Example 2 PPL-catalyzed transesterification of 2-N-benzyloxycarbonyl (Z) serinol (5 of FIG. 4) with vinyl valerate (1e of FIG. 2)
  • R-6 was treated with (+)-2-methoxy-2-(trifluoromethyl)phenylacetyl chloride [(+)-MTPA chloride] and the resulting (+)-MTPA ester (20 mg), which was analyzed by 1H-NMR spectroscopy in the presence of Eu(hfc)3 (80 mg) to establish an enantiomeric excess (ee) greater than 97%.
  • the relative intensities of benzylic methylene group at 4.8 (major) and 4.6 (minor) were measured for ee determination.
  • Example 3 PSL-catalyzed transesterification of seudenol (8a in Table 2) with isopropenyl acetate (1a of FIG. 2)
  • Compound 8a has been used in natural product synthesis via radical-mediated cyclization. Stork, G., Sofia, M.J. J. Am. Chem. Soc. 108 (1986) 6826-28. A solution of isopropenyl acetate (0.44 mL, 4 mmol) and seudenol 8a (224 mg, 2 mmol) in 2 mL of n-hexane was mixed with 3 mg of PSL at 28°C with stirring. After 20 hours, the amounts of seudenol acetate 8b and seudenol 8a were quantitatively determined to be 32:68 by GC analysis.
  • Example 4 PPL-catalyzed transesterification of glycidol (9a in Table 2) with vinyl propionate (1d in FIG. 2)
  • solketal acetate 10b was found to have an optical purity of 65% ee.
  • Solketal acetate 10b 1H-NMR 4.40 (m, 1H), 4.05 (m, 3H), 3.72 (m, 1H), 2.07 (s, 3H), 1.35 (s,3H).
  • Example 6 PSL-catalyzed transesterification of 2-hydroxypropanal dimethyl acetal (11a in Table 2) and 3-hydroxybutanal dimethyl acetal (12a in Table 2)
  • Optically active 11a and 12a of Table 2 are useful as substrates in aldolase-catalyzed synthesis of novel sugars.
  • Durrwachter, J.R., Wong., C-H. J. Org. Chem. submitted.
  • Example 7 PPL catalyzed transesterification of ( ⁇ )-2-octanol (13a of Table 2) with vinyl acetate (1c in FIG. 2)
  • the optical purities of isolated ester 2-octyl acetate (13b in Table 2) and 2-octanol (13a in Table 2) were determined by 1H-NMR spectroscopy in the presence of Eu(hfc)3 (12 mg of acetate, or alcohol was added 84 mg or 72 mg of Eu(hfc)3, respectively).
  • the relative intensities of the methyl groups near the chiral center at 8.72 (major) and 8.64 (minor) (alcohol) and 4.3 (major) and 4.42 (minor) (ester) were used for ee determination.
  • the ester was found to have an optical purity of 98% ee. In a similar manner, the esterification was allowed to proceed at 58% conversion and the unreacted alcohol was isolated.
  • Example 8 PPL-catalyzed transesterification of sulcatol (14a in Table 2) with vinyl acetate (1c of FIG. 2)
  • Compound (S)-14a (Table 2) is a useful pheromone, which has been prepared via lipase-catalyzed transesterification of the racemic alcohol using trichloroethyl propionate and trifluoroethyl laurate.
  • the optical purities of isolated sulcatol acetate and sulcatol were determined by 1H-NMR spectroscopy in the presence of Eu(hfc)3.
  • the relative intensities of methyl group near chiral center at 9.75 (major) and 9.56 (minor) (alcohol) and at 4.92 (major) and 5.02 (minor) (ester) were used for ee determination.
  • the ester was found to have 98% ee.
  • Example 9 PPL-catalyzed transesterification of ferrocenylethanol (17a of Table 2) and vinyl propionate (1d of FIG. 2) in toluene.
  • the resolution of ferrocenylethanol (17a of Table 2) represents an interesting example of enzyme-catalyzed kinetic resolution of chiral organometallic compounds.
  • the ester (17b of Table 2) in aqueous ethanol decomposes via solvolysis to ferrocenylethyl ethyl ether and 17a.
  • the acetate was subjected to SN1 and SN2 displacement.
  • racemic 17a and 17b were obtained.
  • the resolution therefore must be carried out in non-polar aprotic solvents such as toluene.
  • Ferrocenylethanol 17a (0.31 g, mp 70-71°C,[ ⁇ ] D 25 +25.9 (c 1, benzene), lit21 +30.1) prepared by a similar reaction proceeded to 60% conversion.
  • the enantiomeric excesses of ferrocenylethanol 17a and ferrocenylethyl propionate 17b were determined to be 84% and 84%, respectively, with H-NMR in the presence of Eu(hfc)3 (the methyl doublet of ferrocenylethanol 17a at 3.35 ppm and the methyl triplet of the acyl portion of the ester 17b at 2.82 ppm were measured).
  • the relative rates for the hydrolysis of 13b and transesterification of 13a with vinyl acetate and ethyl acetate were found to be 600:55:1.
  • the longer enol esters gave higher enantioselectivity.
  • the lower selectivity in the ethyl acetate reaction may be due to the reversible nature of the reaction.
  • Lipases and cholesterol esterase were found to catalyze enantioselective ester syntheses in various organic media.
  • the leaving groups (acetone and acetaldehyde) of enol esters used in the processes are volatile and easy to remove, making the product separation very simple.
  • vinyl esters were about 20-100 times faster than ethyl esters and about 5 times faster than isopropenyl esters, and generally the long chain esters were faster than short chain esters.
  • vinyl esters reacted 10 times slower. Because the transesterification reaction is carried out in neutral apolar organic solvents, this procedure is suitable for acid-, base- or water sensitive substances.
  • methyl and higher glycosides of hexoses and pentoses are sufficiently soluble in pyridine or other less polar media such that the enzymatic acetylations of these compounds can be accomplished with lipase-catalysis.
  • Stronger solvents such as N,N-dimethylformamide (DMF), dissolve many otherwise insoluble sugars but they also render the lipases inactive. Riva, S., Chapineau, J., Kieboom, A.P.G., Klibanov, A.M. J. Am. Chem. Soc. 110 (1988) 584-589.
  • Protease N neutral protease from Amano International Enzyme Company
  • This enzyme also retains its catalytic activity in dry DMF.
  • Example 10 CCL-catalyzed transesterification of methyl ⁇ -D-glucopyranoside (18a of Table 5) with vinyl acetate (1c of FIG. 2)
  • Methyl ⁇ -D-glucopyranoside (18a of Table 2) (388 mg., 2 mmol) and vinyl acetate (1c of FIG. 2) (4 mmol) were dissolved in 12 mL of benzene - pyridine (2:1). Then 388 mg of CCL was added, and the suspension was stirred at 28°C. After 24 hours, an additional 388 mg of CCL was added, and this was repeated after 48 hours. The suspension was stirred at 28°C for 5 days; then worked up as usual to afford methyl 6-O- ⁇ -D-glucopyranoside 18b as a solid, which was crystallized from ethyl acetate-n-hexane; m.p.
  • Protease N obtained from Amano International Enzyme Co. was used on the following reactions.
  • Other highly stable proteases such as proteases obtained from thermophillic organisms or genetically engineered stable proteases, also could be used in the following reactions.
  • the crude commerical preparation was dissolved in 0.1 M phosphate buffer, pH 7.8 (2 g/35 mL) and lyophilized.
  • the dry powder that was obtained was pulverized with a mortar and pestle prior to use.
  • Protease N from Bacillus subtilis obtained from Amano (2 g) was dissolved in 0.1 mol NaH2PO4 (35 mL), and the resulting solution was stirred for 15 min. The pH was then adjusted to 7.8 with 8.0 NaOH and the solution was freeze-dried. This freeze-dried preparation was used in the synthetic procedure.
  • N-acetyl- ⁇ -D-mannosamine monohydrate (Sigma) (478 mg, 2 mmol) was suspended in anhydrous N N-dimethylformamide (2 mL). Isopropenyl acetate (600 mg, 6 mmol) was added followed by the enzyme preparation (600 mg).
  • Table 7 indicates that, where acetylation occurred, the monoacetyl derivative was predominately formed.
  • the preferential formation of the monoacetyl derivative indicates that the nucleoside was acetylated at the primary (5') hydroxyl group.

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EP93107522A 1988-08-30 1989-08-30 Enantio- und regioselektive Synthesen von organischen Verbindungen mit Enolestern als irreversibele Transacylierungs-Reagenzien Expired - Lifetime EP0560408B1 (de)

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US23835888A 1988-08-30 1988-08-30
US238358 1988-08-30
US07/396,723 US5106750A (en) 1988-08-30 1989-08-24 Enantio- and regioselective synthesis of organic compounds using enol esters as irreversible transacylation reagents
US396723 1989-08-24
EP89115956A EP0357009B1 (de) 1988-08-30 1989-08-30 Methode zur Trennung von Hydroxy-Cyclopentenonen unter Verwendung einer Lipase und Transacylierungsagenzien

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EP89115956.8 Division 1989-08-30

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US5534436A (en) * 1994-03-30 1996-07-09 Chemie Linz Gmbh Enzymatic resolution of asymmetric alcohols by means of vinyl esters of polybasic carboxylic acids
WO2003029477A1 (en) * 2001-09-25 2003-04-10 F. Hoffmann-La Roche Ag Enzymatic process for the preparation of substituted 2-amino-3-(2-amino-phenylsulfanyl)-propionic acid
WO2004080963A1 (en) * 2003-03-13 2004-09-23 Ciba Specialty Chemicals Holding Inc. Process for the preparation of indole derivatives by enzymatic acylation

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US5585252A (en) * 1988-08-30 1996-12-17 G. D. Searle & Co. Enantio- and regioselective synthesis of organic compounds using enol esters as irreversible transacylation reagents
US5827727A (en) 1990-02-01 1998-10-27 Emory University Method of resolution of 1,3-oxathiolane nucleoside enantiomers
US5276151A (en) * 1990-02-01 1994-01-04 Emory University Method of synthesis of 1,3-dioxolane nucleosides
US6642245B1 (en) 1990-02-01 2003-11-04 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane
US5204466A (en) * 1990-02-01 1993-04-20 Emory University Method and compositions for the synthesis of bch-189 and related compounds
US5191109A (en) * 1990-02-02 1993-03-02 Sumitomo Chemical Company, Limited Process for preparing optically active cyclopentenones
CA2039857A1 (en) * 1990-04-26 1991-10-27 Wilfred Po-Sum Shum Process for producing epoxyalcohols of high optical purity
JP3027442B2 (ja) * 1990-10-30 2000-04-04 日東電工株式会社 光学活性エポキシアルコールの製法
ATE141950T1 (de) * 1990-12-24 1996-09-15 Hoechst Ag Verfahren zur acylierung von alkoholen mit einem immobilisierten pseudomonas-lipase
JP3097145B2 (ja) * 1991-02-27 2000-10-10 日産化学工業株式会社 コーリーラクトンジオールの光学分割方法
US5986095A (en) * 1992-01-06 1999-11-16 E.R. Squibb & Sons, Inc. Enantioselective preparation of halophenyl alcohols and acylates
US5447865A (en) * 1992-06-10 1995-09-05 Amprost Pharmaceutical, Inc. Method of resolution of hydroxy substituted cyclopentanone enantiomers using lipase and lithium salt complexation
DE4329293A1 (de) * 1993-08-31 1995-03-02 Basf Ag Lipase katalysierte Acylierung von Alkoholen mit Diketenen
ATE258604T1 (de) 1998-02-17 2004-02-15 Searle & Co Verfahren zur enzymatischen auflösung von laktamen
US5989900A (en) * 1998-08-19 1999-11-23 Development Center Of Biotechnology Process for preparing optically active allylic alcohol derivatives
ES2159231B1 (es) * 1999-04-09 2002-05-16 Smithkline Beecham Sa Procedimiento de resolucion de mezclas enantiomericas de alcoholes catalizada por lipasas.
WO2000068408A1 (de) * 1999-05-05 2000-11-16 Cognis Deutschland Gmbh Verfahren zur selektiven veresterung von polyolen
ES2274854T3 (es) * 2000-05-08 2007-06-01 Pfizer Products Inc. Resolucion enzimatica de moduladores selectivos del receptor de estrogeno.
WO2006054437A1 (ja) * 2004-11-16 2006-05-26 Takasago International Corporation 光学活性化合物の製造方法
US8546114B2 (en) * 2006-01-18 2013-10-01 Chirogate International Inc. Processes for the preparation of optically active cyclopentenones and cyclopentenones prepared therefrom
EP1811037B1 (de) * 2006-01-18 2011-02-23 Shih-Yi Wei Optisch aktiven Cyclopentenonen zur Herstellung von Prostaglandinen
AR071312A1 (es) * 2008-04-09 2010-06-09 Scinopharm Taiwan Ltd Proceso para la preparacion de analogos de prostaglandina y sus intermediarios
ES2574606T3 (es) * 2009-11-26 2016-06-21 National Taiwan University Una sustancia activa contra el cáncer de Antrodia camphorata, método de preparación de la misma y uso de la misma
ES2554563B2 (es) * 2014-05-05 2016-08-16 Universidad De Sevilla Cepas bacterianas y sus usos en reacciones de acilación y/o desacilación
CN114891836A (zh) * 2022-05-31 2022-08-12 重庆张邦医药科技有限责任公司 一种手性二茂铁衍生物的制备方法

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DE4414273A1 (de) * 1994-04-23 1995-10-26 Chemie Linz Deutschland Enzymatische Racematspaltung asymmetrischer Alkohole mittels Vinylestern mehrbasiger Carbonsäuren
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US7011960B2 (en) 2001-09-25 2006-03-14 Hoffmann-La Roche Inc. Substituted 2-amino-3-(2-amino-phenylsulfanyl)-propionic acids
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ATE191509T1 (de) 2000-04-15
DE68913393T2 (de) 1994-07-14
US5106750A (en) 1992-04-21
ES2061844T3 (es) 1994-12-16
EP0357009A3 (en) 1990-12-19
JP2843606B2 (ja) 1999-01-06
EP0357009B1 (de) 1994-03-02
JPH02167098A (ja) 1990-06-27
ES2145017T3 (es) 2000-07-01
EP0357009A2 (de) 1990-03-07
DE68929190D1 (de) 2000-05-11
DE68913393D1 (de) 1994-04-07
KR910004809A (ko) 1991-03-29
DE68929190T2 (de) 2000-09-21
EP0560408B1 (de) 2000-04-05

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